Rebamipide, 2-(4-chlorobenzamido)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid, shown below, is an agent that exhibits anti-inflammatory and antiulcer effects on the gastrointestinal tract.
Rebamipide occurs as a white crystalline powder that is odourless and has a bitter taste. It is very slightly soluble in methanol and ethanol but is practically insoluble in water. Rebamipide is identified by CAS Registry Number: 90098-04-7. A method of preparation of rebamipide is described in JP-B-63-35623.
Rebamipide is known as an agent for improving both subjective and objective symptoms of diseases such as gastric ulcer, duodenal ulcer, gastritis and other like diseases. It has also been disclosed that rebamipide is useful in the treatment of various other diseases, for example, for the treatment a ulcerative colitis (cf., Kazuya Makiyama, “Study of the treatment of ulcerative colitis by enema therapy of rebamipide”), for stomatitis (Japanese Patent No. 2839847), for accelerating salivation (WO/2005/011811) and for inhibiting carcinogenesis of the digestive tract (WO/1997/009045). Rebamipide is also known for having an increasing action of goblet cell density in the eye, an increasing action of mucus in the eye and an increasing action of lacrimal fluid, and it is already known as an agent for treating dry eye (JP-A-9-301866),
Rebamipide is marketed by Otsuka Pharmaceutical Co., Ltd under the Mucosta® tradename. It is currently indicated for the treatment of gastric mucosal legions (erosions, bleeding, redness and edema) in acute gastritis and acute exacerbation of chronic gastritis. The typical dosage in adults is one 100 mg tablet three times daily.
There is a need therefore to develop new forms of rebamipide that have improved dissolution, solubility and/or increased bioavailability. The rebamipide complexes and cocrystals of this invention answer such needs.
Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient (API), the salt and solid state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its pharmacological properties, such as bioavailability, and to its development as a viable API. Recently, crystalline forms of API's have been used to alter the physicochemical properties of a particular API. Each crystalline form of a drug candidate can have different solid state (physical and chemical) properties. The differences in physical properties exhibited by a novel solid form of an API (such as a cocrystal or polymorph of the original therapeutic compound) affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and solubility and dissolution rates (important factors in determining bioavailability). Because these practical physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.
Obtaining crystalline forms of an API is extremely useful in drug development but is not necessarily predictable. It permits better characterization of the drug candidate's chemical and physical properties. It is also possible to achieve desired properties of a particular API by forming a cocrystal of the API and a coformer. Crystalline forms often have better chemical and physical properties than the free base in its amorphous state. Such crystalline forms may, as with the cocrystal of the invention, possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a cocrystal, if achieved, may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising a cocrystal of a given API may have superior properties over its existing drug formulations. They may also have better storage stability.
Another potentially important solid state property of an API is its dissolution rate in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
A cocrystal of any API is a new and distinct chemical composition of the API and the coformer(s) and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer(s) individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques. Cocrystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).